Prognostic Role of NT-proBNP Levels in Empagliflozin-Treated HFrEF

Person with chest pain
3d rendered illustration of a man with chest pain.
The significance of NT-proBNP levels in empagliflozin-treated chronic HFrEF was evaluated in this study.

Higher baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) have been associated with a higher risk for adverse heart failure (HF) outcomes, a risk reduced with empagliflozin therapy regardless of baseline NT-proBNP concentrations. This is according to research results published in the Journal of the American College of Cardiology.

While reductions in NT-proBNP concentration are noted after sodium glucose co-transporter (SGLT2) inhibitor therapy in type 2 diabetes, the significance of NT-proBNP measurements in patients with chronic heart failure with reduced ejection fraction (HFrEF) receiving SGLT2 inhibitor therapy is not well understood.

Researchers therefore set out to evaluate the relationship between NT-proBNP and empagliflozin in the EMPEROR-Reduced Trial ( identifier NCT03057977). EMPEROR-Reduced included patients with HF with left ventricular ejection fraction (LVEF) ≤40% and New York Hospital Association Functional Class II to IV. Participants were randomly assigned in a double-blind fashion to receive either placebo or empagliflozin 10 mg daily. Hospitalization within 12 months of enrollment or elevated NT-proBNP was required for inclusion in the study.

The primary study endpoint was time to first event of composite of CV death or hospitalization for HF. Secondary endpoints included the occurrence of all HF hospitalizations and the slope of the change in estimated glomerular filtration rate (eGFR) during double-blind treatment.

The cohort included 3728 patients with available baseline NT-proBNP data at baseline (median value, 1910 pg/mL; interquartile range [IQR], 1115-3480 pg/mL). Patients with higher NT-proBNP values were older and more medically complex, including higher rates of atrial fibrillation and recent hospitalization, as well as poorer health status.

No significant difference in LVEF was noted across study quartiles.

Across quartiles, investigators noted a clinically meaningful increase in primary endpoint rates; in the placebo group in the highest NT-proBNP quartile, patients had a more than 4-fold higher incidence rate per 100 patient-years for CV death, HF hospitalization, or combined risk for both events. Empagliflozin treatment reduced events across all NT-proBNP quartiles without interaction with baseline levels.

Investigators also noted a stepwise increase in total HF hospitalizations; total hospitalizations doubled across NT-proBNP quartiles among placebo-treated patients, while empagliflozin reduced total hospitalization risk for HF by 30% in the lowest and highest quartiles. Results were similar when all-cause mortality, rather than CV mortality, was used in a joint frailty model (hazard ratios, 0.66, 0.52, 0.84, and 0.73 across quartiles).

Estimated glomerular filtration rate (eGFR) declines were related to baseline NT-proBNP, with the largest decrease in renal function observed in patients with higher NT-proBNP values: mean slope of change among placebo patients in NT-proBNP was -1.65 mL/min/1.73 m2/year and -3.29 mL/min/1.73 m2/year in quartiles 1 and 4, respectively. In each quartile, empagliflozin therapy slowed the rate of eGFR decline with no significant treatment-by-NT-proBNP heterogeneity.

Per researchers, changes in adjusted mean Kansas City Cardiomyopathy Questionnaire Clinical Summary scores were comparable across both study visits and NT-proBNP quartiles.

At 4 weeks after randomization, empagliflozin 10 mg treatment lowered NT-proBNP concentrations (adjusted geometric mean ratio 0.95; 95% CI, 0.92-0.99), a difference that persisted across all study time points but was largest at 52 weeks (0.87; 95% CI, 0.82-0.93).

The researchers also conducted a “landmark analysis” of the change in NT-proBNP from baseline to week 12 in patients who had no primary endpoint events at week 12. In total, 87% of 3730 patients were included in this analysis. Patients in the pooled treatment and placebo groups were categorized by NT-proBNP absolute value at each timepoint and grouped as follows: low/low, high/low, low/high, and high/high.

Analysis results showed that the week 12 risk for CV death or HF hospitalization was lower in patients with NT-proBNP values <1115 pg/mL vs those in higher quartiles. When participants were categorized by baseline and week 12 levels, results indicated that patients were at a lower risk if NT-proBNP was <1115 pg/mL regardless of baseline value.

Compared with the referent high/high category, patients with NT-proBNP <1115 pg/ML by week 12 also had a lower adjusted hazard for CV death and HF hospitalization regardless of baseline value (low/low HR, 0.35; high/low HR, 0.23). For patients who started low but had a 12-week NT-proBNP level of ≥1115 pg/mL, the HR was 0.61 (95% CI, 0.41-0.91).

Results of a model adjusted for age, sex, LVEF, region, diabetes, baseline eGFR, and baseline NT-proBNP found that, compared with placebo, empagliflozin treatment was associated with a 27% higher likelihood of having an NT-proBNP level <1115 pg/mL.

Study limitations include potential bias in resulting from the design, as well as the similarity in primary endpoint results relative to NT-proBNP value whether LVEF was ≤30% or >30%.

 “Treatment with empagliflozin lowered NT-proBNP concentrations, and the achievement of a low-risk NT-proBNP concentration by 12 weeks was more predictive of study endpoints than the baseline NT-proBNP,” the study authors concluded.

Disclosure: This clinical trial was supported by Boehringer Ingelheim and Eli Lilly and Company. Please see the original reference for a full list of authors’ disclosures.


Januzzi JL, Zannad F, Anker SD, et al; for the EMPEROR-Reduced trial committees and investigators. Prognostic importance of NT-proBNP and effect of empagliflozin in the EMPEROR-Reduced trial. J Am Coll Cardiol. 2021;78(13):1321-1332.